Iron deficiency anemia is one of the most common forms of anemia and reduces the efficacy of erythropoietin therapy. Iron deficiency also is induced during the treatment of polycythemia vera because of the block in erythropoiesis induced during iron depletion. The negative effects of iron deficiency override both normal and enforced growth factor signaling. Preliminary data suggests that iron deficiency blocks erythroid differentiation at an early stage by increasing cell death and slowing cell division. To test this hypothesis, we propose two aims to further our understanding. First, we will use a physiologically relevant human peripheral blood stem cell model of iron deficiency to characterize erythroid differentiation, cell cycle effects and apoptosis. Second, we will determine what molecules affect erythropoiesis during iron deficiency. Key molecules known to be important in cell death and survival have been identified in preliminary experiments. The roles that these factors play will be determined by inhibition or add-back experiments using retroviral vectors. These experiments will provide insight into how iron regulates erythropoiesis and may provide novel targets for the treatment of anemia and thrombocytopenia. [unreadable] [unreadable] [unreadable]